The Utility of Sodium Channel Provocation in Unexplained Cardiac Arrest Survivors and Electrocardiographic Predictors of Ventricular Fibrillation Recurrence

Background: The implications of a drug-induced type 1 Brugada ECG pattern following sodium channel blocker provocation (SCBP) are not fully understood. Methods: Baseline clinical and ECG data were obtained from consecutive unexplained cardiac arrest survivors undergoing SCBP at 3 centers. A further 15 SCBP positive (SCBP+) unexplained cardiac arrest survivors were recruited from 3 additional centers to explore ventricular fibrillation recurrence. Results: A total of 121 consecutive unexplained cardiac arrest survivors underwent SCBP. The yield of the drug-induced type 1 Brugada ECG pattern was 17%. A baseline type 2/3 Brugada pattern (T2/3BP) (adjusted odds ratio, 19.36 [2.74–136.61]; P=0.003) and PR interval (odds ratio, 1.03 [1.01–1.05] per ms; P=0.017) were independent predictors of SCBP+ response. A pathogenic SCN5A variant was identified in 36% of the SCBP+ group versus 0% in the SCBP− group (P<0.001). Amongst SCBP+ patients, a spontaneous type 1 Brugada pattern was identified in 19% during follow up and in 24% a type 1 Brugada pattern was identified in a relative. Prior syncope (adjusted hazard ratio, 3.83 [1.36–10.78]; P=0.011) and the presence of global early repolarization (hazard ratio, 7.91 [3.22–19.44]; P<0.001) were independent predictors of 5-year ventricular fibrillation recurrence. There was a nonsignificant trend toward greater 5-year ventricular fibrillation recurrence in the SCBP− group (23/95 [24%] versus 3/34 [9%]; P=0.055). Conclusions: The yield of the drug-induced type 1 Brugada ECG pattern in consecutive unexplained cardiac arrest survivors undergoing SCBP is 17%. A baseline T2/3BP and PR interval were independent predictors of the drug-induced type 1 Brugada ECG pattern. Greater heritability of BrS phenotype in this group was evidenced by a greater prevalence of pathogenic SCN5A variants and relatives with a type 1 Brugada pattern. A history of prior syncope and the presence of global early repolarization were independent predictors of ventricular fibrillation recurrence.

required. In some cases, advanced cardiac imaging with contrast-enhanced cardiac magnetic resonance may identify areas of myocardial fibrosis or motion abnormalities not appreciated on TTE, exercise stress testing, or provocation with epinephrine in those not able to perform exercise stress testing, may unmask long QT syndrome or catecholaminergic polymorphic ventricular tachycardia and sodium channel blocker provocation (SCBP) may identify a concealed form of Brugada syndrome. 1,2 National registry data suggests the yield of the druginduced type 1 Brugada pattern (DI-T1BP) following SCBP with procainamide is 6.9% in cardiac arrest survivors with preserved ejection fraction, 3 while the yield of the DI-T1BP following SCBP with ajmaline has been described in relatives of sudden arrhythmic death syndrome victims, its utility in a large consecutive cohort of cardiac arrest survivors has yet to be reported. [4][5][6][7] Furthermore, the potential for false positives with ajmaline provocation has been highlighted by a Turkish study in which 27.1% of patients with atrio-ventricular nodal re-entrant tachycardia and 4.5% of unrelated controls developed the DI-T1BP following ajmaline provocation. 8 Following the systematic assessment described above, those patients without a reversible metabolic or toxic cause and not fulfilling the diagnostic criteria for a recognized structural or electrical cardiac disorder may be classified as suffering from idiopathic ventricular fibrillation (IVF). The most recent consensus-derived diagnosis of IVF relies on the exclusion of an alternative structural or primary electrical disorder following comprehensive evaluation. 1 A meta-analysis of long-term outcomes in patients with IVF suggests the estimated recurrent event rate may be as high at 31% during an average follow-up period of 5 years. 9 We aimed to determine the yield and significance of the DI-T1BP in a consecutive cohort of survivors with otherwise unexplained cardiac arrest (UCA) undergoing SCBP with either ajmaline or procainamide. We also investigated whether baseline clinical and ECG parameters predict either response to SCBP or the recurrence of VF.

Patient Enrolment
UCA patients were defined as survivors of VF arrest who did not fulfil the diagnostic criteria for a cardiac disorder following: ECG, coronary angiography, cardiac imaging with TTE±cardiac magnetic resonance, and exercise stress testing±epinephrine challenge. Consecutive UCA patients undergoing SCBP were identified at 3 arrhythmia centers: St Georges University Hospital, London, UK; The University of Western Ontario, London, Canada; and the University of British Colombia, Vancouver, Canada. Detailed clinical information and ECGs were shared securely and anonymously with appropriate patient informed consent and local ethical approval was obtained in order to conduct this study. A baseline early repolarization pattern (ERP) was not deemed a contraindication to SCBP and these patients were included in this study. A positive response to SCBP (SCBP+) was defined as the development of the DI-T1BP. The data that support the findings of this study are available from the corresponding author upon reasonable request.
Any future meta-analyses should consider the patients undergoing SCBP with ajmaline as unique to this study; however, a proportion of the patients undergoing SCBP with procainamide have previously been reported as part of earlier registries. 2 • There are concerns regarding the potential for a false positive response to sodium channel provocation with ajmaline. • Previous studies have indicated a significantly higher yield of the drug-induced type 1 Brugada pattern (DI-T1BP) with ajmaline compared to procainamide across a wide clinical spectrum, but there are no direct head-to-head trials.

WHAT THE STUDY ADDS
• Sodium channel provocation in a survivor of an unexplained cardiac arrest may uncover a DI-T1BP in 17%. • In this cohort of patients, there is no statistical difference in DI-T1BP yield between procainamide and ajmaline. • The 5-year ventricular fibrillation (VF) recurrence rate in those with an unexplained VF arrest was 20% and those with a prior history of syncope or global early repolarization are at the greatest risk, but there is no difference in the incidence of VF recurrence between those with the DI-T1BP and those a negative response to sodium channel provocation. • In those with the DI-T1BP, the yield a pathogenic SCN5A variant is identified in 34% and 27% displayed a spontaneous T1BP during follow up.

Electrocardiographic Analysis
A resting supine standard 12 lead ECG obtained during the index presentation and prior to the initiation of drug therapy was analyzed for each patient. ECGs acquired in the immediate period following the VF arrest were excluded to avoid the effects of transient metabolic disturbances. A high right precordial lead ECG was used to exclude the presence of a spontaneous T1BP pre-SCBP; however, lead labeling varied between centers and was not used for the 12 lead ECG analysis. Standard electrocardiographic intervals and durations were measured: RR (ms), PR (ms), QT (ms), Bazetts corrected QTc (ms), and QRS (ms). Brugada type 1 and 2/3 patterns were reported according to the standard definitions 10 (see Figure 1). An early repolarization pattern, ERP, was defined according to the accepted ECG criteria 11 as J-point elevation ≥0.1 mV irrespective of concomitant ST segment elevation and included terminal QRS slurring and QRS notching in an anterior, inferolateral, or global ECG distribution. Quantitively, ST segment elevation was measured at 100 ms after the J-point and was subdivided into upsloping and downsloping ST segment, see Figure 1. Mean ST elevation was calculated according to the ECG lead groups as follows: anterior -V1 to V4; lateral -I, aVL, V5, and V6; inferior -II, III, and aVF.
Early repolarization syndrome (ERS) was defined as, an ERP, as described above, in at least 2 contiguous inferolateral leads in an SCBP− patient. 12

Recurrent Events
In order to investigate VF recurrence, an additional group of SCBP+ UCA survivors were recruited from 3 arrhythmia centers; Imperial College, London, UK; Royal Victoria Hospital, Belfast, UK; and Copenhagen University Hospital, Copenhagen, Denmark. These UCA survivors underwent an identical investigative pathway as those in the consecutive cohort.

Statistical Analysis
Data were analyzed with IBM SPSS Statistics version 27. Categorical variables were compared using the χ 2 or Fisher exact test where appropriate. The Kolmogorov-Smirnov test was used to test the distribution of data. Normally distributed continuous variables were analyzed using a Students T test and are reported as mean (±SD) The Mann-Whitney was performed to compare differences between nonnormally distributed continuous variables, which are reported as median [1st quartile to 3rd quartile].
A univariate analysis for the response to SCBP in the consecutive cohort and recurrence of VF in the final overall cohort was performed. Variables demonstrating significant association on univariate analysis (P<0.10) were included in a multivariable logistic regression model.
Future event rates are reported as the proportion of the cohort experiencing the primary end point (first implantable cardiac defibrillator [ICD] shock for VF) over a 5-year follow-up period. Those not followed up beyond index presentation were not included in the analysis. A Cox proportional hazards model was used to analyze VF recurrence over a 5-year follow-up period. Hazard ratios (HRs) and 95% CIs are presented. A value of P<0.05 was considered statistically significant. Cumulative hazard rates were plotted against time from initial presentation.

RESULTS
We identified 121 consecutive UCA survivors undergoing SCBP: the consecutive cohort. An additional 15 December 2022 826 SCBP+ UCA survivors from the 3 additional centers were included in the final overall cohort and were included in the analysis of VF recurrence. Table 1 describes the consecutive cohort. Univariate and multivariable regression analyses for factors associated with SCBP+ response are shown in Figures 2 and 3, respectively.
Across the entire cohort, all patients underwent coronary assessment and a TTE. Two patients were unable to exercise and underwent epinephrine provocation with no finding. A cardiac magnetic resonance was performed in 125 of 136 patients (91.9%) and no major or diagnostic abnormalities were identified. In the 9 patients without cardiac magnetic resonance, the resting TTE was normal.
There was a family history of sudden cardiac death in a 1st or 2nd degree relative in 6 of 21 (29%) SCBP+ patients versus 1 of 100 (1%) SCBP− patients, P<0.001. In addition, prior to presentation, 2 of 21 (10%) SCBP+ patients had a family history of BrS. In contrast, there were no SCBP− patients with a family history of BrS, P=0.002. Subsequent familial evaluation revealed a DI-T1BP in a relative in 3 of 21 (14%) SCBP+ patients versus 2 of 100 (2%) Fifty-one patients in the consecutive cohort (42%) underwent provocation using ajmaline, while 70 of 121 (58%) patients were investigated with procainamide.
In the multivariable logistic regression model (Figure 3), a baseline T2/3BP was an independent predictor of the positive response to SCBP (adjusted OR, 19 Figure 5).
Cumulative 5-year survival analysis for SCBP outcome, prior syncope, and global ER are shown in Figure 6.

DISCUSSION
In this multicenter retrospective study, we identified 121 consecutive patients undergoing SCBP after UCA. The overall yield of the DI-T1BP was 17.3% with no significant difference between ajmaline (22%) and procainamide (14%). The presence of a baseline T2/3BP was a strong and independent predictor of SCBP+ response (DI-T1BP), as was PR interval (ms). Across the entire final cohort, 20% experienced a recurrence of VF over a 5-year follow-up period with a trend toward an increased risk of recurrence in the SCBP− group. A history of prior syncope and the presence of an ERP in a global distribution on the baseline 12-lead ECG were independent predictors of VF recurrence.

False Positive or True Positive?
Currently, a DI-T1BP and a history of aborted cardiac arrest are sufficient to make a diagnosis of BrS and thus 21 of 121 patients (17%) of our cohort fulfilled this criterion. 13,14 However, considering the reported potential for false positive outcomes with SCBP, 8 especially with ajmaline, we sought to provide additional evidence in support of a true positive result and diagnosis of BrS in those developing the DI-T1BP.
First, 36% of the SCBP+ patients in our study were found to have pathogenic SCN5A variants following clinical genetic testing. This is higher than the overall reported yield of 20% to 25%. The utility of genetic testing in those without a diagnosis following an UCA is limited, as such only 43% of our SCBP− cohort underwent In accordance with the current guidance, screening with SCBP in family members of our SCBP+ patients was undertaken consistently, and we observed a DI-T1BP in at least one relative in 14% of this group. In contrast, the extent of phenotypic evaluation in the SCBP− cohort varied and while we observed the DI-T1BP in only 2 relatives of separate unrelated SCBP− patients, the yield may have been higher if SCBP had been systematically applied in this group. These 2 cases have previously been described in a study by Mellor et al. 15 In families 2 and 3 of this study, a relative of the UCA survivor was found to have a type 2 BrS on subsequent family screening, which converted to a T1BP with ajmaline. In both cases, SCBP in the UCA survivor was repeated and remained negative. Overall, Mellor et al identified a DI-T1BP in at least one family member in 12 UCA probands giving an overall positive rate of 25% (3/12) at the family level. Whether this represents a false positive DI-T1BP in the relative or a false negative in the UCA survivor is difficult to determine. This outcome may be affected by several factors, including the age of the UCA victims, all <21 years of age. Variable expressivity mediated by common genetic variation or environmental factors might influence the outcome of SCBP in these subjects. 16 While we also observed that 10% (2/21) of SCBP+ patients had a family history of BrS prior to presenting with an UCA, neither of these subjects had previously been screened for BrS. There was no prior history of BrS in the SCBP− group.
Overall, 19% (4/21) of the SCBP+ cohort were found to have a spontaneous T1BP observed on a resting ECG during follow up, as opposed to ambulatory ECGs. Gray et al 17 reported a burden of the spontaneous T1BP in patients with a DI-T1BP of 34% (11/32). However, the utility of a high lead ambulatory ECG recording in a patient already receiving an ICD is uncertain and was thus not performed routinely in our study. The presence of a spontaneous T1BP, however, strengthens the diagnosis of BrS in a fifth of our SCBP+ cohort.
Taken together these data support an enrichment of the DI-T1BP group for BrS as a diagnosis, although in the absence of a gold standard, the possibility of false positives and false negatives remains.

Ajmaline Versus Procainamide
While there is no direct head-to-head or cross over trial data, previous studies have reported a consistently higher yield of the DI-T1BP with ajmaline in comparison with procainamide across clinical indications. Papadakis et  In this current study, the yield of the DI-T1BP observed in the group receiving procainamide was higher than previously reported with this SCBP agent in similar cohorts, and while the trend to a higher yield with ajmaline continued, this was not statistically significant. This may suggest that the yields of the 2 agents are comparable when applied to those deemed to carry the greatest a priori chance of having a more penetrant form of BrS, that is, presenting with an otherwise unexplained cardiac arrest.
There were no other differences in the clinical characteristics in ajmaline-SCBP+ and procainamide-SCBP+ patients, with similar yields following genetic testing and familial evaluation. There was a trend toward a greater proportion of procainamide SCBP+ patients having a family history of BrS, but this was not significant. A spontaneous T1BP was seen during follow-up in an ajmaline-SCBP+ patient more frequently than in a procainamide-SCBP+ patient, but this was not statistically significant.

SCBP Positive Versus SCBP Negative:
Electrocardiographic Comparisons SCBP+ patients, as expected, displayed a higher prevalence of the T2/3BP at baseline, a greater mean ST elevation (mm) in the anterior leads and longer mean PR (ms) intervals and mean QRS (ms) durations, while SCBP negative patients demonstrated a greater mean lateral ST elevation (mm). Baseline T2/3BP and an increasing PR interval, a novel finding, were independent predictors of the positive response to SCBP.
Prolongation of the QRS duration and PR interval have previously been reported in patients with BrS and are both associated with an increased incidence of major arrhythmic events (syncope, ventricular tachycardia, VF, and appropriate ICD shocks). [18][19][20][21][22] The association between major arrhythmic events and QRS duration and PR interval prolongation in BrS patients in general appears to be irrespective of genetic status; however, a relationship between SCN5A pathogenic variants and cardiac conduction disease in BrS is well described. 18,23 However, all patients in our series had already suffered a cardiac arrest. These ECG parameters, therefore, appear less relevant as risk makers for recurrence of VF.
Five-year VF recurrence rates, time to recurrence, and estimated 5-year cumulative survival rates were statistically comparable between the 2 groups, although there was trend toward greater risk of 5-

Early Repolarization
The first description of ERS relied on the presence of elevation of the QRS-ST segment ≥1 mV in at least 2 contiguous leads in patients with UCA. 24 Subsequent electrocardiographic refinement included an assessment of the ST segment slope, upsloping or downsloping, with the latter having a greater arrhythmic risk especially if located in the inferior and or lateral leads in the general population 25 and a greater risk of VF recurrence in UCA survivors. The current consensus definition accepts that an ERP may exist in the absence of ST segment elevation if there is J point elevation >0.1 mV either as a notch or as slurring within the terminal QRS 11 (central illustration). In our study, 22% of the SCBP− group had inferolateral ER >2 contiguous leads on the baseline ECG at presentation and would therefore fulfil the current consensus definition of ERS. 13 However, a similar proportion of the SCBP+ group also displayed baseline inferolateral ER, 24%, P=0.695.
Antzelevitch et al 26,27 have previously sought to classify ER into subtypes based on spatial distribution and increasing arrhythmic risk with type 1 being benign ER isolated to the lateral precordial leads, type 2 associated with a greater risk and present in the inferolateral leads, type 3 showing a global distribution, and type 4 being J-point elevation related to the DI-T1BP.
We explored the influence of the individual components of ER. Mean lateral ST segment elevation was significantly greater in the SCBP− group in contrast to a greater degree of anterior ST elevation in the SCBP+ group. The pattern of distribution of ST segment elevation was comparable between the groups; however, the SCBP− group demonstrated a trend toward a greater prevalence of global ST segment elevation, which was the only electrocardiographic feature with a significant independent association with VF recurrence. This is consistent with type 3 ERS described by Antzelevitch et al. However, the HRs for VF recurrence were comparable between the upsloping and downsloping subtypes of ST elevation. This differs from prior work by Rosso et al, 28 although the comparator group was an athletic control and the patient group was smaller than that presented here.

Syncope
While the overall prevalence of prior syncope across the entire population was low (8%), it did prove to be an independent predictor of VF recurrence across our population (adjusted HR, 3.83 [1.36-10.78], P=0.011). The prevalence of syncope pre-enrolment in BrS registries has been reported to be between 21% and 34%. [29][30][31][32] However, much of these data are from those without prior cardiac arrest. Nevertheless, in those with syncope, a significantly higher incidence of VF or appropriate ICD therapy was observed.
The Cardiac Arrest Survivors With Preserved Ejection Fraction Registry reported a higher prevalence of prearrest syncope than that observed in our study; 35% across the entire cohort and 32% in those in whom the final diagnosis was IVF and 37% in those with an alternative diagnosis. 2 However, a recent subgroup analysis by Steinberg et al 33

Clinical and Mechanistic Implications
The development of a DI-T1BP in UCA survivors does not appear to be associated with an increased risk of further VF and one could argue that the utility of SCBP in this setting is therefore limited. However, with 14% of SCBP+ patients having at least one relative with a DI-T1BP on subsequent cascade screening, as well as the greater prevalence of a FH of sudden cardiac death and BrS and pathogenic genetic variants, SCBP remains an important tool in the identification or exclusion of a heritable trait. Previous work by Nademanee et al, 34 in a cohort of patients with recurrent VF, ER ± co-existing Brugada ECG patterns, identified the presence of epicardial low voltage and fractionated late potentials in the RVOT and inferolateral RV in those exhibiting both patterns. The timing of these late potentials corresponded to the presence of J point elevation on the surface ECG (predominantly in the inferolateral leads) and subsequent substrate ablation resulted in a drastic reduction in VF recurrence. We observed a similar inferolateral distribution of J-point ST segment elevation in 28% of our final cohort, which was associated with an increased risk of VF recurrence within the 5-year follow-up period in the univariate analysis (HR, 2.49 [1.15-5.38]; P=0.021).
Histopathologic assessment of biopsied tissue from a patient with ERS identified extensive myocardial fibrosis, which corresponded with fractionated potentials, delayed activation, and repolarization abnormalities during epicardial mapping of the inferior right ventricular free wall, which were associated with an ER pattern on the surface electrocardiogram. 35 Ablation of these regions resulted in a reduction in arrhythmia recurrence and normalization of the ECG. Furthermore, genetic studies have shown that SCN5A pathogenic variants are important in ERS as well as BrS patients. Zhang et al 36 reported a 10% yield of likely pathogenic and pathogenic SCN5A variants in a cohort of ERS probands compared with a yield of 23% in BrS probands. Similarities in the clinical and demographic characteristics between these groups were noted but electrocardiographic differences with the BrS SCN5A positive probands demonstrating significantly longer QRS durations, shorter PR intervals, longer QTc intervals, and a lower prevalence of bradycardia compared to the ERS SCN5A positive group. Interestingly, the authors also described a patient with a fever-induced ERS phenotype with a SCN5A pathogenic variant and fever-induced BrS phenotype in another patient with the same variant.
The evidence suggests that ERS and BrS may in part share common histopathological substrates and mechanisms for arrhythmogenesis, which are manifested by J-wave changes on the surface ECG. Our study suggests that the location and extent of these J waves, some of which may be augmented by SCBP challenge and some not, appears to determine the risk of recurrence of VF. We, therefore, need to change our approach to the categorization and management of UCA patients as syndromes, and better understand the underlying epicardial substrate of the J wave syndrome. In this way, we will be able to manage patients for their individual risk for VF and recurrence and offer catheter ablation of substrates in an effective way.

Study Limitations
The centers participating in this study are either national or regional referral centers for inherited arrhythmia syndromes. There may be patients referred with an UCA in whom we were able to find a cause without the need for SCBP. These patients were not included in this study. Additionally, it would be difficult to determine whether there were eligible UCA patients who were not referred. As such the true number of patients presenting with an UCA is unknown and we were unable to provide any prevalence data.
While statistical power may be a potential reason for the lack of statistically significant associations for certain analysis. The number of patients in the SCBP+ and VF recurrence groups were small and represented <20% of the total cohort. This may overestimate the strength of the effect in the multivariable analysis; however, there are few comparable studies of this size investigating similar cohorts or phenotypes in this manner.
While our cohort of patients were thoroughly investigated at the point of presentation, there is evidence to support the late development of structural disorders in patients given an initial diagnosis of IVF. 37 We report on recurrent event rates our cohort, but data regarding the evolution of structural disorders were not available.

Conclusions
This study has identified a 17% of the DI-T1BP in consecutive UCA survivors undergoing SCBP, with no significant difference observed between SCBP agents. The presence of a baseline T2/3BP was an independent predictor of a DI-T1BP as was an increasing PR interval suggesting a greater degree of conduction abnormality in this group. Prior syncope and global ER were independent predictors of VF recurrence. A DI-T1BP response did not, however, show an independent association with recurrence but may be a marker of a more heritable form of the condition. This may be consistent with the accumulating view that many IVF survivors share a similar